The cervical epithelial barrier
In the laboratory, meanwhile, we are learning how certain microbes are mechanistically involved in the pathogenesis of sPTB. Research over the last decade has suggested that disruption or breakdown of the cervical epithelial barrier drives cervical remodeling processes that precede sPTB. The question now is, do cervicovaginal bacteria associated with sPTB, or a nonoptimal cervicovaginal microbiota, cause disruption of the vaginal and cervical epithelial barrier – and how?
Using an in vitro model system, we found that Mobiluncus curtisii/mulieris, the bacterial taxa with the strongest association with sPTB in our Motherhood & Microbiome cohort and one that has long been associated with bacterial vaginosis, had a plethora of effects. It increased cell permeability and the expression of inflammatory mediators associated with cervical epithelial breakdown, and it altered expression of microRNAs that have been associated with sPTB in human studies.
Our study on Mobiluncus has served as proof of concept to us that, not only is the bacteria associated with sPTB, but that there are multiple mechanisms by which it can disrupt the cervicovaginal barrier and lead to cervical remodeling.5
The findings echo previous in vitro research on Gardnerella vaginalis, another anaerobic bacterium that has been associated with bacterial vaginosis and adverse obstetric outcomes, including sPTB.6 Using similar models, we found that G. vaginalis disrupts the cervical epithelial barrier through diverse mechanisms including the cleavage of certain proteins, the up-regulation of proinflammatory immune mediators, and altered gene expression.
Lactobacillus crispatus, on the other hand, conferred protection to the cervical epithelial barrier in this study by mitigating various G. vaginalis–induced effects.
Learning more about host-microbe interactions and the role of microbial metabolites in these interactions, as well as the role of altered gene expression in cervical function, will help us to more fully understand the biological mechanisms regulating cervicovaginal epithelial cells. At this point, we know that, as in the gut, bacteria commonly found in the cervicovaginal space play a significant role in regulating the function of epithelial cells (in both optimal and nonoptimal microbiota), and that various bacteria associated with sPTB contribute to poor outcomes by breaking down the cervical epithelium.
Therapeutic implications
Our growing knowledge of the cervicovaginal microbiota does not yet support screening or any particular interventions. We don’t know, for instance, that administering probiotics or prebiotics orally or vaginally will have any effect on rates of sPTB.
Ongoing research at all levels holds promise, however, for the development of diagnostics to identify women at risk for sPTB, and for the development of therapeutic strategies that aim to modify the microbiome and/or modify the immune response. We know from other areas of medicine that there are realistic ways to modulate the immune response and/or microbiota in a system to alter risk.
We need to more thoroughly understand the risk of particular microbiota and immune response factors – and how they vary by race and ethnicity – and we need to study the cervicovaginal microbiota of women before and during pregnancy to learn whether there is something about pregnancy or even about intercourse that can change one’s microbiome to a less favorable state.
It may well be possible in the near future to identify high-risk states of nonoptimal microbiota before conception – microbiota that, in and of themselves, may not be pathogenic but that become detrimental during pregnancy – and it should be possible to screen women early in pregnancy for microbial or immune signatures or both.
The question often arises in medicine of the validity of screening without having achieved certainty about treatments. However, in obstetrics, where we have different levels of care and the ability to personalize monitoring and care, identifying those at greatest risk still has value. Ultimately, with enough investment in all levels of research (basic, translational, and clinical), we can develop interventions and therapeutics that address a biologically plausible mechanism of sPTB and, as a result, achieve significant reductions in the rate of prematurity.
Dr. Elovitz is the Hilarie L. Morgan and Mitchell L. Morgan President’s Distinguished Professor in Women’s Health, vice chair of translational research, and director of the Maternal and Child Health Research Center, department of obstetrics and gynecology, at the University of Pennsylvania, Philadelphia. She disclosed holding a patent on a method to determine risk of preterm birth that relates to the microbiome. Email her at obnews@mdedge.com.
References
1. JAMA. 2017 Mar 14;317(10):1047-56.
2. NIH Human Microbiome Project. https://hmpdacc.org/.
3. PNAS. 2011 Mar 15;108 (Supplement 1):4680-7.
4. Nat Commun. 2019 Mar 21. doi: 10.1038/s41467-019-09285-9.
5. Anaerobe. 2019 Nov 21. doi: 10.1016/j.anaerobe.2019.102127.
6. Front Microbiol. 2018 Oct 8. doi: 10.3389/fmicb.2018.02181.